A great percentage of the elderly population is at the risk of a vertebral fracture due to osteoporosis. Fractures of thoracic 12 and lumbar 1 constitute the majority of these vertebral fractures. External factors, such as loading, being aside, bone quality is the major determinant of a fracture. The measure of bone quality that is relevant to fracture is bone strength. However, current measures of bone quality, such as bone mineral density, are only surrogates of bone strength and have variable diagnostic success. New technologies with potentially high diagnostic value that are under development make use of the observation that bone stiffness and strength are highly correlated, i. e., how much load the bone can carry before fracture is related to how flexible the bone is under a given load. How these two apparent properties are related through bone's microstructural organization and to what extent bone stiffness is related to bone strength are very fundamental questions of bone biology. We believe that the close relationship between the apparent strength and apparent stiffness of cancellous bone is a result of an adaptation where tissue (trabeculae) stress magnitude and variability is controlled through microstructural organization such that the average and the scatter of the tissue stresses are correlated. This project will determine the relationships between bone microstructure, tissue stress distributions and bone apparent properties at a tissue and organ level for T4-L5 vertebrae from human spines using microcomputed tomography, large-scale finite element analysis and mechanical testing. The results of this project will reveal: (i) whether greater levels of damaging stresses are generated in the tissue from T12-L1 junction independent of external factors, (ii) whether the association between tissue stresses and bone apparent properties is sensitive to the choice of within-patient and between-patient samples, (iii) microstructural features of bone that give rise to damaging forms of stresses in the tissue, and (iv) whether vertebral bone strength at the organ level can be predicted by stiffness measurements using the concepts introduced for cancellous bone tissue. The long-term goal of this research is to enhance our ability to diagnose and develop strategies for prevention of bone disease and failure through a better understanding of the stress-regulated structure of vertebral bone.